Tumors are imprinted by their immune environment, and this imprinting facilitates their transformation into populations that can more effectively resist the pressure exerted by the subject's immune system to eradicate them. The immune system can act both positively to inhibit the progression of tumors and negatively to mold the establishment of tumors that can evade its recognition, or worse to promote the advancement of tumor development. This process by which the immune system can prevent or promote tumor progression is referred to as immunoediting (Schreiber R D et al, 2011, Science, 331(6024):1565-70; Scarlett U K et al, 2012, J. Exp. Med., 209(3):495-506).
Adoptive cell transfer therapy (ACT) or Adoptive T cell therapy is the ex vivo activation, expansion, and subsequent administration of tumor-reactive T cells. Adoptive T cell therapies have focused on the use of CD8+ T cells, as they have relatively long clonal expansion times, can specifically target tumors, and are easily subjected to genetic manipulations. Adoptively transferred tumor-specific T cells can also be expanded from resected tumors before being genetically manipulated. Under ideal circumstances, transferred T cells migrate to the tumor site and directly lyse tumor cells, while releasing endogenous immune cells from tumor-induced immunosuppression. However, the tumor environment is usually so immunosuppressive that it is difficult to appropriately release these brake mechanisms on antitumor responses.
Adoptive T cell therapy, while highly successful for many nonepithelial cancers, has not yet been effective in the most frequent and aggressive epithelial cancers, including ovarian carcinoma (see, e.g., Kershaw, M. H. et al. 2006 Clin Cancer Res 12, 6106-15; see also, Dudley M E et al 2002 Science 298, 850-4; Bollard, C M et al 2007 Blood, 100:2838-45; Leen, A M et al 2006 Nat. Med., 12:1160-6). Tumor-reactive T cells properly conditioned ex vivo have the capacity to induce significant therapeutic effects against preclinical models of established ovarian cancer (Nesbeth Y, S. Y., et al, 2009 Cancer Res. 69, 6331-38; Nesbeth, Y. C. et al. 2010 J Immunol 184, 5654-62). Nevertheless, in these studies, anti-tumor T cells did not persist for long periods and, despite a significant survival increase, mice eventually succumbed to the disease, suggesting that the activity of transplanted T cells was suboptimal. This lack of success is likely due to the complexities of the tumor microenvironment, which apparently causes the rapid disappearance of transferred lymphocytes. Supporting this proposition, the responsiveness of tumor-reactive T cells in lymph nodes draining established tumors is severely impaired during tumor progression (PMID: 22351930).
Further, the ability to produce large numbers of tumor-reactive T cells is hampered because not only do they usually occur in only low frequencies, but also most T cells that robustly respond to self-antigens have either been eliminated during thymic development or rendered nonfunctional by local tolerizing mechanisms.
There remains a need in the art for effective adoptive immunotherapy mechanisms for the successful treatment of a variety of cancers.